DESCRIPTION (Applicant's Abstract): The central nervous system (CNS) and immune system engage in reciprocal communication. Sleep is a fundamental CNS process that is regulated by neurotransmitters and responds to immune challenge, as evidenced by changes in sleep that occur when we are sick. In this application we focus on interactions in brain between serotonin (5-hydroxytryptamine; 5-HT) and interleukin-1 (IL-1) as representatives of neurotransmitters and immune-active molecules that are involved in sleep regulation. We previously investigated IL-1 effects on 5-HT and showed that sleep responses to IL-1 are altered if the 5-HT system is antagonized. Studies proposed in this application focus on the reciprocal interaction, i.e., 5-HT effects on IL-1. Our central hypothesis is that, serotonergic activation stimulates the somnogenic cytokine IL-1, which may be one of the factors through which 5-HT exerts its effects on sleep. This central hypothesis will be addressed within the framework of the following questions. 1) Does serotonergic activation alter the brain IL-1 system? 2) Are 5-HT effects on sleep altered when the brain IL-1 system is antagonized? 3) Is the preoptic area/anterior hypothalamus (POA) an important site for these interactions? These questions will be addressed using behavioral, electrophysiological, and molecular approaches. Our preliminary data from the rat indicate that serotonergic activation increases NREM sleep, IL-1 mRNA expression, and c-fos activity in the hypothalamus. These new results and those of previous studies indicate that interactions between these two systems are functionally relevant to sleep. 5-HT and IL-1 are involved in the regulation in the regulation of a number of physiological functions and behaviors in addition to sleep. As such, although our focus remains firmly on sleep, the integrated experimental approach we propose will result in information relevant to several fields of basic and clinical neuroscience.